Viruses are implicated in a variety of animal and human diseases. Numerous approaches have been proposed to combat these pathogens which include, but are not limited to, herpesviruses 1 and 2 (HSV 1 and HSV-2), influenza viruses A, B and C (orthomyxoviruses), parainfluenza viruses 1-4, mumps virus (paramyxovirus), adenoviruses, respiratory syncytial virus, Epstein Barr virus, rhinoviruses, human immunodeficiency viruses (HIV), polioviruses, coxsackieviruses, echoviruses, rubella virus, varicella-zoster virus, neurodermotropic virus, variola virus, cytomegalovirus, hepatitis A, B and non-A, non-B viruses, papoviruses and rabies virus.
One approach in the development of antiviral compounds has been to identify compounds which interfere with the normal viral metabolism of nucleosides. Because the structures of these compounds are usually closely related to nucleosides which occur naturally in the mammalian host, few have good activity against the virus without untoward side effects. Some of the few compounds having activity are very expensive to produce. Thus, there is a continuing need for new compounds which act to kill viruses, to inhibit viral replication or to block the pathogenic actions of viruses.
The following references disclose various carbocyclic analogs of nucleosides: Ichikawa, et al., European Patent Application No. EP0330992, published Sep. 9, 1989, discloses 2-hydroxy-3-hydroxymethylcyclobutyl substituted purines and pyrimidines having antiviral activity; Zahler, et al., European Patent Application No. EP0322854, published Jul. 5, 1989, discloses 2-hydroxy-3-hydroxymethylcyclobutyl substituted purines and pyrimidines having antiviral activity; Slusarchyk, et al., European Patent Application No. EP0335355, published October 4, 1989, discloses 2,3-bis(hydroxymethyl)cyclobutyl substituted purines and pyrimidines having antiviral activity; Tolman, et al., U.S. Pat. No. 4,782,062, issued Nov. 1, 1988, discloses 9-((Z)-2-(hydroxymethyl)cyclobutylmethyl)guanine as a viral thymidine kinase inhibitor;
Kjellin, et al., U.S. Pat. No. 4,644,001, issued Feb. 17, 1987, and U.S. Pat. No. 4,548,818, issued Oct. 22, 1985, disclose cyclopropyl , cyclobutyl and cyclopentyl substituted purine analogs which are useful for treating obstructive airway disease or cardiac disease;
Maccoss, et al., European Patent Application No. EP0184473, published June 11, 1986, discloses 2-amino-9-((2)-2-(benzoyloxymethyl)cyclobutylmethyl)-6-benzoylpurine;
Albrecht, et al., U.S. Pat. No. 3,923,792, issued Dec. 2, 1975, discloses cyclopropyl-, cyclopropylmethyl and cyclopentyl-substituted cytosine analogs which are useful as antibacaterial agents;
Albrecht, et al., U.S. Pat. No. 4,016,267, issued Apr. 5, 1977, discloses cyclopropyl-, cyclopropylmethyl- and cyclopentyl-substituted nucleoside analogs which are useful as antibacaterial agents;
Ashton, et al., U.S. Pat. No. 4,617,304, issued Oct. 14, 1986, discloses ((hydroxymethylcyclopropyl)methyl)-substituted purine and pyrimidine analogs as antiviral agents;
Temple, et al., J. Med. Pharm. Chem. 5 866 (1962), discloses cyclopropyl-substituted purine analogs which are useful for treating human epidermal carcinoma; Masoliver, et al., C.A. 107:236375e, Spanish Patent No. ES519898, published Mar. 16, 1984, discloses cyclopropylmethyl-substituted purine analogs; and Marquez, et al., Medicinal Research Reviews, 6 1-40 (1986) discloses substituted-cyclopentyl nucleoside analogs.